Venous thromboembolism (VTE) is a common condition causing substantial morbidity, cost and mortality, yet several aspects of the epidemiology of this disease remain unexplored. The major aim of this proposal is to evaluate potentially modifiable lifestyle predictors of VTE and their joint associations with biochemical and genetic determinants. Studies will identify determinants of both initial occurrence of VTE as well as recurrence among persons with a prior event. The study design is a prospective cohort study of 77,118 persons based on pooling information from four large randomized trials of US health professionals that have collected detailed risk factor information and have used common strategies to prospectively identify and validate cases of VTE. These trials are: Physicians' Health Studies I and II including 29,071 US male physicians, of whom 22,071 have been followed since the initiation of the first trial in 1982; the Women's Health Study including 39,876 female health professionals who will have an average of 10 years of follow-up; and the Women's Antioxidant Cardiovascular Study including 8,171 female health professionals with prevalent cardiovascular disease or at high risk of cardiovascular disease who will have an average of 8 years of follow-up. Archived blood samples were collected from approximately 75 percent of participants at baseline and will be used to assess biochemical and genetic markers of risk including factor V Leiden, the G20210A mutation in the prothrombin gene, hyperhomocysteinemia, and anticardiolipin antibodies. The study will assess the joint association with risk of these markers and potentially modifiable factors including body mass index, hormone replacement therapy, physical activity, and aspirin use. The study population will include over 1,000 incident cases of VTE, including 750 with blood samples. The large size, prospective design, high follow-up rates, detailed and reliable long-term exposure and outcome information, and the availability of blood specimens on a large subgroup, combined with the relatively low cost, make these cohorts a valuable and unique resource for studying determinants of risk of VTE. The results of this work may lead to new strategies for VTE preventio.